Abstract

Electroconvulsive therapy (ECT) is an effective treatment for major
depression. Optimising efficacy and minimising cognitive impairment are goals
of ongoing technical refinements.

Aims

To compare the efficacy and cognitive effects of a novel electrode
placement, bifrontal, with two standard electrode placements, bitemporal and
right unilateral in ECT.

Method

This multicentre randomised, double-blind, controlled trial (NCT00069407)
was carried out from 2001 to 2006. A total of 230 individuals with major
depression, bipolar and unipolar, were randomly assigned to one of three
electrode placements during a course of ECT: bifrontal at one and a half times
seizure threshold, bitemporal at one and a half times seizure threshold and
right unilateral at six times seizure threshold.

Results

All three electrode placements resulted in both clinically and
statistically significant antidepressant outcomes. Remission rates were 55%
(95% CI 43–66%) with right unilateral, 61% with bifrontal (95% CI
50–71%) and 64% (95% CI 53–75%) with bitemporal. Bitemporal
resulted in a more rapid decline in symptom ratings over the early course of
treatment. Cognitive data revealed few differences between the electrode
placements on a variety of neuropsychological instruments.

Conclusions

Each electrode placement is a very effective antidepressant treatment when
given with appropriate electrical dosing. Bitemporal leads to more rapid
symptom reduction and should be considered the preferred placement for urgent
clinical situations. The cognitive profile of bifrontal is not substantially
different from that of bitemporal.

Electroconvulsive therapy (ECT) is widely considered to be the most
effective treatment for severe major depression. However, there continues to
be controversy in the field about optimal methods for administering the
treatment. In particular, electrode placement, that is, the anatomic location
of the stimulus electrodes on the individual’s scalp, has been the
subject of debate for more than 60
years.1–7
This debate centres around the balance of the antidepressant efficacy of the
treatment against the cognitive effects it produces. Numerous
studies8–10
and a
meta-analysis11
have concluded that right unilateral ECT is moderately less effective than
bitemporal ECT and that it causes fewer cognitive effects. Recently, however,
study data suggest that right unilateral electrode placement must be delivered
at multiples of seizure threshold to be maximally
effective.6,10,12
Thus, much of the literature prior to 2000 contains results that are biased
against efficacy in right unilateral
placement.6 A novel
placement, bifrontal, has recently gained popularity in clinical practice
because it is reported to be equally efficacious to bitemporal placement, but
with fewer cognitive
effects.8,13
The significance of the cognitive effects of ECT as a basis for electrode
selection remains highly
controversial.14
Some experts contend that these effects are of little importance compared with
the often dramatic lifesaving effects of the
treatment.15 Yet,
cognitive effects are the main impediment to the broader application of
ECT.16,17
To our knowledge, no prior study has directly compared bitemporal, bifrontal
and right unilateral ECT. We carried out a multisite, randomised, clinical
trial using modern state-of-the-art ECT techniques and comprehensive masked
assessments to address the above issues.

Method

Overview

The participating centres (University of Medicine and Dentistry of New
Jersey-New Jersey Medical School, Medical University of South Carolina, The
Zucker-Hillside Hospital Northshore-Long Island Jewish Health System,
University of Texas Southwestern Medical Center at Dallas and Mayo Clinic)
comprise the Consortium for Research in ECT
(CORE).18,19
This study was a multicentre, National Institute of Mental Health
(NIMH)-funded, randomised, double blind, controlled trial carried out from
2001 to 2006 (NCT00069407). A total of 230 people with acute depression, both
bipolar and unipolar, were randomly assigned using a permuted
block-randomisation scheme to one of three electrode placements during an
acute course of ECT: bifrontal at one and a half times seizure threshold,
bitemporal at one and a half times seizure threshold, and right unilateral at
six times seizure threshold. Participants were treated until they achieved
pre-specified remission criteria and then were followed naturalistically for 2
months. A comprehensive neurocognitive battery was performed at baseline,
after the fourth ECT, after the last ECT and at 1 week and 2 months after the
last ECT. This protocol was reviewed and approved by the institutional review
boards of all five participating academic clinical centres. Participants
provided informed consent prior to study entry. This paper reports results for
the active treatment (randomised) phase of the study.

Participants

Participants were between 20 and 87 years old, referred for ECT, currently
depressed and met Structured Clinical Interview for DSM–IV
(SCID–I)20
criteria for primary major depressive disorder or bipolar disorder, with or
without psychosis. Appropriateness for ECT was determined on a clinical basis
after consultation with an attending-level ECT psychiatrist. Typical reasons
for referral included multiple failed medication trials and severity/urgency
of illness. Additional inclusion criteria were pre-treatment Hamilton Rating
Scale for Depression–24 item
(HRSD–24)21
total score ≥21, ability to cooperate in detailed neuropsychological
testing, and to provide voluntary written informed consent.

Exclusion criteria were a lifetime diagnosis of schizophrenia,
schizoaffective disorder or intellctual disabilities, recent (within the last
year) diagnosis of anxiety disorder, obsessive–compulsive disorder,
eating disorder that preceded the current episode of depression, current
diagnosis of delirium, dementia, amnestic disorder or other central nervous
system disease with the probability of affecting cognition or response to
treatment, diagnosis (within 6 months) of active substance misuse/dependence,
medical conditions contraindicating ECT, Mini-Mental State Examination
(MMSE)22 score ≤
21 and ECT in the 6 months prior to the study.

Electrode placements

One of the following three electrode placements was used, depending upon
the participant’s group assignment: bifrontal, in which the centre of
each electrode was placed 4–5 cm above the outer canthus of the eye
along a vertical line perpendicular to a line connecting the
pupils;8 bitemporal,
in which the centre of the stimulus electrodes was applied 2–3 cm above
the midpoint of the line connecting the outer canthus of the eye and the
external auditory meatus on each side of the individual’s head; and
right unilateral, in which one electrode was positioned as in bitemporal on
the right side (d’Elia
placement).23 The
centre of the other electrode was placed 2–3 cm to the right of the
vertex of the skull. Standardisation of placement was assured by training of
study psychiatrists at the initial investigators’ meeting, use of an
illustrative figure in each treatment suite and site visits by the study
principal investigator.

ECT procedures

ECT procedures were standardised across all centres, using the Thymatron
DGx ECT device (Somatics LLC, Lake Bluff, Illinois, USA), dose titration to
determine seizure threshold at initial treatment and stimulus dosing at
subsequent treatments as follows: one and a half times seizure threshold for
bifrontal and bitemporal, six times seizure threshold for right unilateral (or
at 100% of device maximum when six times seizure threshold could not be
reached). Details of the stimulus algorithm used in the dose titration
procedure to determine seizure threshold are shown in
Table 1. Treatments were given
three times a week, as is the clinical custom in the USA.

Procedures for anaesthesia and determination of seizure adequacy
(electromyography (EMG) ≥20 sec; electroencephalogram (EEG)≥25) followed
standardised clinical protocols compatible with current standards of
care.5 Anaesthesia
management consisted of pre-treatment with glycopyrrolate, followed by
induction with an anaesthetic agent (methohexital for 135 participants,
thiopental for 75 participants, etomidate for 14 participants and propofol for
6), followed by succinylcholine for muscle relaxation. Participants were
oxygenated throughout the procedure with 100% O2 with positive
pressure delivered through a disposable bag and mask. Blood pressure, heart
rate and pulse oximetry were monitored. Electroencephalogram was recorded from
a single channel using left frontomastoid placements. Motor duration of
seizures was recorded using a two-lead EMG from the right foot.

Masking procedure for electrode placements

In order to ensure that participants were unaware of which electrode
placement was used, each person was prepared for all three types of electrode
placement. This included placement of disposable electrode pads in bifrontal
and bitemporal positions, and application of electrode gel to the vertex
position. Only after the individual was unconscious was the designated
electrode placement implemented.

Assessments

Instruments

The primary instrument used to rate depressive symptoms was the
HRSD–24 administered at baseline and prior to each ECT treatment. The
impact of electrode placement on neurocognitive performance was measured by an
extensive battery of neuropsychological tests. The cognitive domains studied
included orientation/global status, memory (verbal and non-verbal, anterograde
and retrograde) and executive function. The specific instruments in the test
battery were: the Mini-Mental State Examination (MMSE); the Rey Auditory
Verbal Learning Test
(AVLT);24,25
the Rey Osterrieth and the Taylor Complex Figure
Tests;26,27
Autobiographical Memory Interview – Short Form
(AMI–SF);28
the Trail Making
Test,29 Category
Fluency,30 the
Stroop Color Word
Test,31–33
the Controlled Oral Word Association Test
(COWAT),30 the
Delis–Kaplan Executive Function System (D–KEFS) Sorting
Test34 and the
Reading subtest of the Wide Range Achievement Test
(WRAT–3).35
Reorientation score 20 min after ECT was measured using a ten-question
instrument, modified from an instrument previously used by the Columbia
University group.36
Global functioning was assessed using the Clinical Global Impression (CGI)
scale.37

Raters

The raters who acquired study data were the study psychiatrist, the
continuous rater and the neuropsychological technician. At specified time
points (baseline and after the last ECT), the continuous rater and study
psychiatrist each performed independent HRSD–24 ratings, with the mean
of the ratings used for analyses. Raters were masked to treatment
condition.

Outcome assessment

We used the longitudinal profile of continuous HRSD–24 total scores
over the ECT treatment course (approximately three times a week) as one
efficacy outcome. Other efficacy outcome measures were the single
end-of-treatment HRSD–24 score and the proportion of remitters for each
electrode placement group. The end-of-treatment HRSD–24 was obtained
within 24–36 h after the final ECT, or as soon thereafter as possible.
Remitter criteria were: a ≥60% decrease from baseline in HRSD–24
total score; HRSD–24 ≤10 on two consecutive ratings; and
HRSD–24 did not change >3 points on the last two consecutive
treatments. A specific minimum or maximum number of ECT was not required for
an individual to be classified as a remitter. People who did not meet
remission criteria and who received at least ten treatments were declared
non-remitters. Participants were considered to have dropped out of the study
if consent for ECT or study participation was withdrawn before ten ECT had
been administered or initial seizure threshold was 80% or higher, or ECT was
discontinued for clinical reasons before ten ECT had been administered.
Response was defined as a decrease in HRSD–24 total score of 50% from
baseline.

Statistical analyses

All statistical tests were carried out using SAS version 9.13 for
Windows.

Missing data

Missing data occurred for the continuous HRSD–24 outcome if the
participant did not return for the final HRSD–24 assessment within
24–36 h after the final ECT. Because there was no prescribed number of
ECT for remitters, the final ECT was the last treatment received regardless of
time in the study. Analyses involving the full longitudinal profile of
HRSD–24 values did not require imputation of missing values because the
analysis method (mixed effects modelling) can accommodate missing data. For
analyses of the single end-of-treatment measure, the HRSD–24 obtained
immediately prior to (e.g. on the morning of) the final ECT was used as the
missing end-of-treatment value. This occurred for 40 participants (17%).
Missing outcomes for neurocognitive test battery results were imputed using
multiple imputation (SAS Proc MI).

Efficacy analyses

The efficacy analyses used a modified intent-to-treat (ITT) sample
comprising all randomised participants who had at least one post-baseline
assessment. In analyses of the continuous efficacy outcome, the longitudinal
trajectories of HRSD–24 scores over the treatment course were compared
among electrode placement groups using a mixed effects modelling approach (SAS
Proc Mixed).38 The
auto-regressive covariance structure was used because it resulted in the best
fit for the mixed effects modelling. A series of models was evaluated
beginning with the simple model containing only treatment, time and treatment ×
time interaction effects as independent variables (simple or
unadjusted model). Addition of psychosis status, polarity, age and clinical
centre to the mixed effects modelling provided a comparison of electrode
placements adjusted for these covariates (adjusted model). Psychosis status,
polarity and clinical centre were included as covariates because they were
stratification variables in the randomisation. In addition, we explored
inclusion of a random intercept and a quadratic time trend in the model. Both
the linear and quadratic terms in the polynomial model were statistically
significant and the quadratic model (simple and adjusted) was used as the
final analysis model. Pair-wise comparisons of mixed effects modelling least
squares means were adjusted using the Tukey–Kramer multiple comparison
procedure.

In another set of analyses, the mean end-of-treatment HRSD–24 total
scores (single end-point) were compared among the treatment (electrode
placement) groups using a general linear models approach. The adjusted general
linear model contained the same covariates as described for mixed effects
modelling and post hoc pair-wise comparisons of least squares means
between electrode placement groups were carried out using the
Tukey–Kramer multiple comparison procedure.

Paired t-tests were used to evaluate change from baseline within
each electrode placement group.

Remission proportions were estimated for each electrode placement using 95%
confidence intervals. For the repeated measures (longitudinal) analyses, we
have 90% power to detect a standardised effect size of approximately
0.24–0.32 standard deviations in pair-wise comparisons between electrode
placement groups (assuming two-sided level of significance α = 0.05,
number of repeated measures: six based on average number of ECT administered,
and intraclass correlation (ICC) ranging from 0.3 to 0.7). Based on our
estimated common pooled standard deviation for HRSD–24 total scores of
8.87, this is equivalent to a raw effect size that can be detected of
2.1–2.8 units on the HRSD–24 scale. For the continuous single
end-point HRSD–24 outcome, the study had 85% power to detect effect
sizes of approximately 4.5 HRSD–24 units (0.5 standardised units) or
higher.

Cognitive analyses

The continuous end-of-active treatment neuropsychological variables were
analysed using the multivariable general linear models approach (SAS Proc GLM
(general linear model)). The adjusted general linear model contained the
baseline level of the given instrument, age, gender, psychosis, polarity,
clinical centre, last HRSD–24 and WRAT–3 as covariates. The last
HRSD–24 score was used to adjust for level of illness severity at the
time the neuropsychological variables were assessed. The WRAT–3 was
included as a measure of pre-treatment intellectual functioning. Post
hoc pair-wise comparisons of least squares means between electrode
placement groups were carried out using Tukey’s multiple comparison
procedure. The cognitive analyses have 85% power to detect standardised effect
sizes in pair-wise treatment comparisons ranging from 0.5 to 0.6 for imputed
sample sizes ranging from approximately 70 (MMSE) to 56 (D–KEFS) per
group. Sample sizes per instrument differed based on number of participants
missing baseline levels for a given instrument, and therefore eliminated from
the modified ITT sample size for the cognitive analyses of that
neuropsychological variable. The amount of missing data that required
imputation for the neuropsychological instruments ranged from 35 to 55% by the
end of acute treatment. The percentage missing baseline data for the
instrument (and hence eliminated from the imputed data-set) ranged from 9 to
25%. Missingness for these variables was largely attributable to participant
refusal or lack of time to administer the battery. Although multiple
imputation methods were used to impute the missing values, caution is
exercised in the interpretation of the cognitive results because of the amount
of data that had to be estimated, as well as the missing baseline values.

Results

Participant flow and characteristics

Figure 1 describes the flow
of participants through the study. A total of 274 people were entered into the
study; 37 screen failures were excluded after entry so 237 people were
randomised. Of these, 7 had no post-baseline assessment, yielding a modified
ITT efficacy evaluable sample of 230 individuals: 77 right unilateral, 81
bifrontal and 72 bitemporal. Among the modified ITT sample, 63 of 230
participants (27.4%) exited the study early. There were no statistically
significant differences in demographic or baseline clinical characteristics
between completers and those who dropped out.

The rate of drop out was similar across all three groups; 31.2% for right
unilateral, 27.2% for bifrontal and 23.6% for bitemporal (P = 0.581).
Major reasons for dropping out across the three treatment groups were
confusion/cognitive impairment (19.3%), ECT not working (17.5%), non-cognitive
side-effect (7.0%) and improvement in condition (5.3%). There were no
statistically significant differences between the groups for any of these
reasons for drop out.

For the ITT sample, 63.5% were female, 95.5% were White and the mean age
was 53.1 (s.d. = 15.0) years. Of the sample, 23.5% had psychotic features and
22.7% had bipolar depression. The mean baseline HRSD–24 score was 34.6
(s.d. = 7.2). There was no difference in psychosis status, polarity and
baseline HRSD–24 between the groups
(Table 2).

Participant characteristics for the intent-to-treat sample and by
treatment

Efficacy results

The change in HRSD–24 outcomes from baseline to the end of treatment
within each electrode placement group demonstrated that all three placements
were highly effective treatments. The mean change from baseline for
HRSD–24 total scores (baseline to end) was greater than 20 points in all
three groups (P<0.0001, all groups by paired t-test;
Table 3).

The trajectory of observed means over the ECT treatment course is
demonstrated in Fig. 2. The
trajectory is steep for all placements up to visit six (after five ECT). The
flattening of the trajectories after approximately six ECT (visit seven)
reflects the relatively early remissions for all placement groups (among 137
remitters, 74% of bitemporal, 69% of right unilateral and 59% of bifrontal
achieved remission with six or fewer ECT).

In mixed effects modelling longitudinal analyses of trajectories of
HRSD–24 total scores over the ECT treatment course, there was a
significant downwards trend for all electrode placements in the unadjusted and
adjusted polynomial models (coefficients for linear and quadratic time effects
for both models: Ps<0.0001)
(Fig. 3). The model-fitted
HRSD–24 means for bitemporal placement were significantly lower than
those for right unilateral at visits two to eight (after ECT one to seven).
The difference in covariate-adjusted HRSD–24 means between the
bitemporal and right unilateral placements was approximately three
HRSD–24 units over these time periods (visit two: difference in least
squares means effect size (ES) = 2.54, Tukey–Kramer adjusted P
= 0.058); visit three: ES = 2.90, adjusted P = 0.016; visit four: ES
= 3.14, adjusted P = 0.013; visit five: ES = 3.25, adjusted
P = 0.016; visit six: ES = 3.26, adjusted P = 0.022; visit
seven: ES = 3.13, adjusted P = 0.037; visit eight: ES = 2.88,
adjusted P = 0.085). The HRSD–24 means for bitemporal placement
were significantly lower than those for bifrontal at visits three to five
(after ECT two to four) (visit three: ES = 2.45, adjusted P = 0.047;
visit four: ES = 2.60, adjusted P = 0.046; visit five: ES = 2.51,
adjusted P = 0.081). The HRSD–24 means did not differ
significantly for right unilateral compared with bifrontal placement at any
time point. Among those who remitted, almost all (≥90%) of the remissions
occurred within approximately 3 weeks of treatment (≤9 ECT). Participants
remaining in the study up to visit nine were predominantly those for whom none
of the treatments were effective (non-remitters). In further mixed effects
modelling analyses, we restricted interest to the time period in which the
early rapid decrease in symptoms occurred (e.g. after approximately 2 weeks of
treatment). For this period, the rate of decrease in HRSD–24 scores for
the bitemporal placement was significantly greater than that for right
unilateral, indicating a more rapid rate of symptom reduction for this
placement (bitemporal v. right unilateral: P = 0.029/0.026
for linear/quadratic terms in adjusted mixed effects modelling). Further, the
bifrontal placement produced a decrease in symptom severity that was
marginally significantly better than that of right unilateral over the early
treatment period (bifrontal v. right unilateral: P =
0.109/0.084 for linear/quadratic terms in adjusted mixed effects
modelling).

After only one ECT, there was a 10.6 (s.d. = 8.6) point reduction, on
average, in symptom severity (decline in HRSD–24 total scores) for the
three electrode placements combined. This early reduction in symptom severity
after only one ECT represented approximately 48% (10.63/22.29) of the total
decline in HRSD–24 scores over the full treatment period. The reduction
in severity after one ECT within each electrode placement was: right
unilateral 44.1% (9.28/21.03); bifrontal 47.7% (11.17/23.40); bitemporal 51.1%
(11.45/22.40). The decline in HRSD–24 total scores after the first ECT
was marginally greater for bitemporal compared with right unilateral
(bitemporal v. right unilateral, P = 0.073 from general
linear models adjusted for baseline HRSD–24, age, clinical centre,
psychosis status, polarity). Comparisons of these early declines for right
unilateral v. bifrontal and for bitemporal v. bifrontal were
not statistically significant (right unilateral v. bifrontal,
P = 0.251; bifrontal v. bitemporal, P = 0.791, from
covariate-adjusted general linear models)

Considering the single end-of-treatment value for all participants
(remitters, non-remitters, individuals who dropped out), there were no
statistically significant differences between HRSD–24 end scores among
electrode placement groups after adjustment for baseline HRSD–24, site,
age, psychosis and polarity (right unilateral: 13.1 (95% CI 11.1–15.2);
bifrontal: 11.5 (95% CI 9.5–13.5); and bitemporal 11.4 (95% CI
9.3–13.5), P = 0.418, general linear models analyses). It
should be noted that the study was adequately powered to detect effect sizes
for the continuous single end-point HRSD–24 outcome of approximately 4.5
HRSD–24 units or higher. The effect sizes that can be detected with the
longitudinal analyses are smaller than those for single end-point analyses for
a given level of power.

Table 4 and
Fig. 4 present remission
outcomes at the end of the acute course of ECT for each electrode placement.
Based on 95% confidence interval estimation, population remission proportions
for right unilateral were estimated to range from 43 to 66%; for bifrontal
estimates range from 50 to 71%; and for bitemporal, the estimates range from
53 to 75%. These remission proportion confidence interval estimates apply to
the potential population of all individuals who may receive the treatments,
taking into account the uncertainty in the sampling process. Post hoc
power analyses for the remission outcomes indicate low power for detecting
significant differences between electrode placement groups, therefore
attention should be focused on estimation of the proportions via 95%
confidence intervals rather than hypothesis testing (P-values).

The mean number of ECT among remitters was 5.9 (s.d. = 2.3) for right
unilateral, 6.2 (s.d. = 2.6) for bifrontal and 5.5 (s.d. = 2.3) for bitemporal
placement (P = 0.405 from general linear models).

Cognitive results

There were no significant differences between the electrode placement
groups for the instruments measuring overall global cognitive function (MMSE)
and executive function (Category Fluency, COWAT, Stroop, Trail Making A, B and
D–KEFS) (Tables 5 and
6). Bifrontal placement was
statistically significantly inferior to bitemporal on two measures of
anterograde memory (AVLT 1–5, AVLT Delay) and showed a trend towards
inferiority (P = 0.10) on a measure of anterograde memory (AVLT%) and
retrograde amnesia (AMI). Right unilateral placement was not statistically
significantly superior to the bilateral placements on any of these cognitive
measures.

Reorientation score at 20 min measured at ECT session one was statistically
better for right unilateral v. the other two electrode placements
(right unilateral: 8.0 (s.d. = 3.1); bifrontal: 4.6 (s.d. = 3.6); and
bitemporal: 6.0 (s.d. = 3.9); right unilateral v. bifrontal
P<0.0001, right unilateral v. bitemporal P =
0.007; and bitemporal v. bifrontal P = 0.091; from general
linear model adjusted for site and age with Tukey correction for multiple
comparisons). Since ECT session one is the dose titration session, right
unilateral is not administered at close to the stimulus dose (six times
seizure threshold) used at subsequent treatments. Reorientation score at 20
min after ECT session two showed that right unilateral maintained its
advantage over bifrontal (right unilateral: 5.9 (s.d. = 3.3); bifrontal: 4.3
(s.d. = 3.0) (P = 0.010)), but was not statistically different from
bitemporal placement (bitemporal: 5.8 (s.d. = 3.4) (P = 0.952)).
Bitemporal was statistically superior to bifrontal in reorientation score
after treatment session two (P = 0.026). Averaged across all ECT
sessions, but excluding ECT session one, the three electrode placements were
not statistically different, but their relative order remained the same as for
ECT session two (right unilateral: 5.7 (s.d. = 2.5); bitemporal: 5.5 (s.d. =
2.8); bifrontal: 4.8 (s.d. = 2.5); right unilateral v. bifrontal
P = 0.113; right unilateral v. bitemporal P =
0.901; bitemporal v. bifrontal P = 0.267, from general
linear models adjusted for site and age with Tukey correction for multiple
comparisons).

Discussion

Efficacy

Each electrode placement resulted in clinically and statistical
significance decreases in depression severity. Bitemporal electrode placement
resulted in a more rapid decrease in symptom severity, early in the course of
treatment. Each of the three placements resulted in a substantial decrease in
symptoms with the initial treatment.

These results are consistent with several decades of data comparing
antidepressant outcomes between bitemporal and right unilateral placement, and
add important data about the more recently developed bifrontal placement. Two
other randomised controlled trials that compared right unilateral
(administered in a similar way to the present study) and bitemporal remission
rates 1 week after the ECT course also found inferior rates for right
unilateral placement (60% v.
65%,10 59%
v.
65%)9,39
that did not reach statistical significance. Our right unilateral efficacy
data should be interpreted in the context of its administration at the six
times seizure threshold, a relatively recent technical enhancement that is
believed to optimise this electrode placement. It should also be noted that US
ECT devices are limited to a charge output of under 600
mC,40 preventing a
small number of the participants (5/77, 6.5%) in this study from being treated
at fully six times seizure threshold. Both bilateral placements resulted in
slightly, but not significantly, superior remission proportions than right
unilateral placements. It is possible that with increased power to detect
differences with an even larger sample size, a potentially meaningful clinical
difference favouring the bilateral placements would also become statistically
significant. Based on our results, particularly the superior speed of response
seen with bitemporal electrode placement, it is appropriate to continue the
preferential use of bitemporal electrode placement in more urgent clinical
situations. Such situations might include high suicide risk, severe medical
comorbidities and catatonia. On the other hand, right unilateral at high
stimulus doses should be considered an effective form of ECT. When the
practitioner and individual are most concerned about minimising retrograde
amnesia, right unilateral may be the preferred initial choice, given the
accumulated evidence in the literature of its more benign cognitive profile.
The suggestion by
Prudic17 that right
unilateral electrode placement may be more rapidly effective than bitemporal
was not supported by our findings.

Our data demonstrating the substantial impact on depressive symptoms of the
initial treatment in the series are also consistent with prior reports in the
literature.41–43
However, the fact that right unilateral placement was administered at a near
threshold dose (the first treatment was the one at which the dose titration
procedure to estimate seizure threshold was carried out) is intriguing, given
observations that right unilateral may need to be given at multiples of
seizure threshold to insure
efficacy.10,12

Cognition

Our cognitive function data reveal few differences between the electrode
placements on a variety of neuropsychological instruments. Bifrontal electrode
placement was developed upon the theoretical assumption that moving the
stimulus electrodes farther from the temporal lobes (particularly the
hippocampi) would result in less memory impairment. On the other hand, seizure
initiation from the frontal lobes beneath the bifrontally placed electrodes
might be theorised to produce more executive dysfunction. Our data neither
confirm a memory advantage for bifrontal (in fact, on some measures they show
a disadvantage), nor a disadvantage for executive functioning. Bifrontal
placement has become quite commonly used based on prior reports of its
efficacy and side-effect
profiles8,13
and also because of its ease of use in practice. However, the evidence base in
the literature for bifrontal remains much smaller than that for either
bitemporal or right unilateral, and some would continue to regard it an as
experimental placement.

Right unilateral electrode placement was developed based upon the
theoretical assumption that sparing the language centres of the left
hemisphere the direct passage of the electrical stimulus would result in less
cognitive impairment. Surprisingly, in our study, right unilateral was not
consistently superior to bitemporal except for reorientation 20 min after ECT.
Sobin et al suggest that speed of reorientation after ECT is a proxy
for longer term memory
impairment.36 Our
failure to find a consistently superior cognitive profile for right unilateral
placement may be a result of administering right unilateral at high stimulus
doses, a technique that may diminish the cognitive advantages of this
placement when administered at lower stimulus
doses.44 We cannot
eliminate the possibility that failure to find a cognitive advantage of one
placement over another may be the result of undetected bias caused by
differential rates of drop out in those participants with the worst cognitive
outcomes. Further study to better characterise the specific cognitive profile
of each electrode placement is clearly warranted, including more frequent
measurement time points, and longer study periods to characterise the time
course of resolution of cognitive effects. We advocate the development of a
streamlined, ECT-specific neuropsychological assessment battery that requires
a considerably shortened administration time, and can be administered
concurrent with the illness symptom severity instruments. This would allow the
concurrent tracking of illness severity and cognitive changes, and potentially
would allow disentangling of these effects. Further, a considerable reduction
in administration time should dramatically reduce the amount of missing data
resulting in more reliable cognitive results.

Limitations

Failure of the study to find statistically significant differences for both
efficacy and cognitive outcomes cannot be taken to mean that the outcomes in
the two groups are equal. Lack of such differences could be the result of low
statistical power, particularly for the cognitive outcome variables for which
sample sizes were substantially reduced.

Implications

Our data add to the evidence base that right unilateral at six times
seizure threshold and bifrontal and bitemporal at one and a half times seizure
threshold are all highly efficacious electrode placements for use in ECT for
the treatment of major depression. Practitioners may be reassured that each
standard electrode placement in contemporary ECT practice, when given with
appropriate electrical stimulus dosing, is a highly effective antidepressant
technique. Because bitemporal placement results in more rapid depressive
symptom reduction, it is the preferred electrode placement when the clinical
situation requires urgent improvement. Our data do not support a cognitive
advantage of bifrontal over bitemporal placement.

Funding

C.H.K. research support from the National Institute of
Mental Health (NIMH), loan of ECT device
from Somatics LLC (no monies involved). M.M.H. research support from the
NIMH,
Stanley Medical Research Institute,
Cyberonics, Inc, Magstim, Neuronetics and Advanced
Neuromodulations Systems (ANS). S.M.M., K.G.T and C.M.
research support from the
NIMH. G.P. research
support from AstraZeneca, Novartis, Corcept,
NIMH. This study was
supported by the NIMH
(NCT00069407).